The hydroxyl group(s) may occur at various
positions in the carbon chain which can be saturated or monoenoic.
Some polyhydroxy fatty
acids are also known, which are most frequently produced by lipoxygenase
activities, as for several mono-hydroxylated fatty acids.
In some bacteria, complex hydroxy, branched-chain fatty acids (mycolic acids)
are described.

MONOHYDROXY FATTY ACIDS

a-Hydroxy
acids or 2-hydroxy acids are found in plants (chain from 12 up to
24 carbon atoms) and in animal wool waxes, skin lipids and specialized tissues,
mainly in brain.
2-Hydroxylinolenic acid was reported at a level of 13% in the seed oil
of the Labiateae Thymus vulgaris (Smith CR et al., Lipids 1969,
4, 9). Along with the previous one, 2-hydroxylinoleic and 2-hydroxyoleic
were detected in another Labiateae Salvia nilotica (Bohannon MB et
al., Lipids, 1975, 10, 703). Several 2-hydroxy fatty acids have been reported
to be present in polar lipids of the alga Grateloupia turuturu from Britany,
France (Kendel
M et al., Lipids 2013, 48, 535).
2-Hydroxytetracosanoic acid (cerebronic acid) and 2-hydroxy-15-tetracosenoic
acid (hydroxynervonic acid) are constituents of the ceramide
part of cerebrosides (glycosphingolipides found mainly in nervous tissue and
in little amount in plants).

The testis and
spermatozoa of boar and rat contain sphingomyelin with 2-hydroxylated n-6 tetra-
and pentaenoic acids with very long carbon chain (up to 34 carbon atoms) (Robinson
BS et al., J Biol Chem 1992, 267, 1746). It has been postulated that
these lipids play a role in reproduction.

Several studies have uncovered potent biological activities of 2-hydroxyoleic
acid (Minerval). This synthetic derivative of oleic acid was found to have
potent anti-cancer activities in vitro and in animal models (Martinez
J et al., Mol Pharmacol 2005, 67, 531; Llado
V et al., J Cell Mol Med 2010, 14, 659). The anti-cancer activity of
2-hydroxyoleic acid is mediated, at least in part, by downregulation of
dihydrofolate reductase (Llado
V et al., PNAS 2009, 106, 13754). The mechanism of its action is not
fully understood, and it has been attributed to its structural effects on cell
membranes, rather than specific interactions with target proteins. Nevertheless,
it seems that the pro-apoptotic activity of 2-hydroxyoleic
acid explains the effectiveness of this non-toxic anticancer drug (Llado
V et al., J Cell Mol Med 2010, 14, 659).
New results have shown that this fatty acid is able to regulate the synthesis of
sphingomyelin in glioma cells in restoring normal membrane levels and triggering
cell cycle arrest (Barcel-Coblijn
G et al., PNAS 2011, 108, 19569).

2-Hydroxy-9-cis-octadecenoic acid

The
addition of 2-hydroxy palmitic acid to different cell lines increased their
sensitivity to the synthetic antitumor drug, PM02734 (Herrero
AB et al., Cancer Res 2008, 68, 9779).
A review of fatty acid 2-hydroxylation in sphingolipid biology in connection
with the nervous system and various cell types may be consulted (Hama
H, Biochim Biophys Acta 2010, 1801, 405). Curiously, among the enantiomers,
the (R)-enantiomer is enriched in hexosylceramide whereas the (S)-enantiomer
is preferentially incorporated into ceramide (Guo
L et al., J Lipid Res 2012, 54, 1327).

Polyhydroxyalkanoates : The
chemical composition of lipid inclusions in Bacillus megaterium was identifed
in 1926 as poly(3-hydroxybutyric acid) (Lemoigne M, Bull Soc Chim Biol 1926,
8, 770). Since that discovery, a
large variety of bacteria were shown to synthesize polyesters (polyhydroxyalkanoates)
forming linear chains of esterified 3-hydroxy acids (Kim YP et al., Adv Biochem
Eng Biotechnol 2001, 71, 51). More than 90 different monomer units have
been identified as constituents of polyhydroxyalkanoates in various bacteria.
A few members include poly(3-hydroxybutyrate) or poly(3-hydroxybutyrate-co-3-hydroxyvalerate.
They are sometimes, but erroneously, considered to be a carbohydrate, but their
solubility characteristics are those of a lipid, except for high molecular weight
homopolymers of 3-hydroxybutyrate units which are acetone-insoluble.

Poly(3-hydroxybutyrate)
is the most widespread and best characterized lipid polymer. These polyesters accumulate as
intracellular inclusions and act as a carbon and energy reserve. They are produced by some bacteria when they have extra energy, then used as an energy source when needed.
They have a
great industrial interest because of their plastic and elastomer properties and
as a source of biodegradable polymers for low-value commodity products. Their
synthesis in crop plants would allow an efficient large-scale production which
may lead to new substitutes for petroleum-derived plastics (Rezzonico E et
al., Phytochemistry Rev 2002, 1, 87). Genetic engineering has been done to transfer the polymer-making capacity to
Escherischia coli and to higher plants. It is theoretically possible to modify starch forming plants (such as potatoes) to grow
these polymers.
Several lipid-like fractions (acetone-soluble) are copolymers containing both
short- and medium-chain-length 3-hydroxyalkanoate units. They have been identified as various hydroxyalkanoic
acids with 3 to 14 carbon atoms (Steinbuchel A, 1991,
Polyhydroxyalkanoic acids. In: Byrom D (ed)Biomaterials.
Macmillan, New York, p 123). Two groups of bacteria have been described :
those which produce short-chain polyhydroxyalkanoates (C3-C5 monomer units) and
those producing medium-chain polyhydroxyalkanoates (C6-C14 monomer units). Some
bacteria (Rhodospirillum, Rhodocyclus, Rhodococcus, Aeromonas, Pseudomonas)
have been shown to accumulate polyesters containing short- and
medium-chain-length 3-hydroxyalkanoic
acids. A copolymer with a molecular mass of about of 40 000 containing
3-hydroxybutyric acid (3HB) and several other 3-hydroxyalkanoic acids has been
described in Pseudomonas sp (Kato M et al., Appl Microbiol Biotechnol
1996, 45, 363). A part of the described structure is shown below.

Applications
are being developed to produce and extract these bacterial polymers for use in
industry, including molded goods, paper coatings, non-woven fabrics, adhesives,
films, and polymer additives. The biocompatible nature of polyhydroxyalkanoates
and their potential applications in the medical field should also not be
overlooked. Biodegradable plastics and polymers are certain to increase in
importance as environmental contamination and waste disposal problems associated
with synthetic plastics become more severe. Metabolix Inc. of Cambridge, Mass
USA, has taken up the challenge to further
develop efficient technologies for polyhydroxyalkanoates
production (http://www.metabolix.com/index.html).

b-Hydroxy
acids
or 3-hydroxy acids occur
in some bacterial lipids.
3-Hydroxy oxylipins are widely distributed in nature,
occurring in mammals, bacteria and yeasts. In mammalian systems, production of
3-hydroxy oxylipins is mainly attributed to fatty acid oxidation disorders.
Since 3-hydroxy fatty acids are unique structural
components of the endotoxin (LPS), characteristic of Gram-negative bacteria, they can
be employed as biomarkers for estimating the amount of these bacteria in
atmospheric aerosols (Lee
AKY et al., Atm Envir 2004, 38, 6307). Nevertheless, there are limitations
in their use when analyzing animal tissues since they are also produced by
mitochondrial beta-oxidation (Szponar B et al., J Microbiol Meth 2002, 50,
283). Chemically, endotoxin is lipopolysaccharides
which is a major constituent of the outer membrane of Gram-negative bacteria.
The lipid portion of the endotoxin, lipid A, is chemically distinct from all
other lipids in biological membranes and consists of characteristic 3-hydroxy
fatty acids, primarily with carbon chain lengths from 10 to 18, attached to
hydroxyl and amino groups of a disaccharide backbone. It has been proposed
that 3-hydroxy fatty acid quantification may be employed as biomarkers of
endotoxins and Gram-negative bacterial community in atmospheric aerosols (Lee
AKY et al., Atmosph Environ 2004, 38, 6307). This approach is more
iformative than the determination of mass loading, total endotoxin concentration
in aerosols.
The LPS layer is not limited to bacteria. The presence of this cell wall
component has been reported in a medically important higher basidiomycete, Antrodia
camphorata (Cheng
J. et al., J Agric Food Chem 2005, 53, 469), this fungal LPS reversing
the immuno-regulating properties exerted by bacterial LPS.
It must be noticed that 3-hydroxypalmitic acid methyl ester has been shown to be
a very potent autoregulator compound controlling virulence in the
phytopathogenic bacterium Ralstonia solanacearum (Flavier
AB et al., Mol Bacteriol 1997, 26, 251). This fatty acid methyl ester
was shown to be an intercellular signal active via a volatile phase.

3-Hydroxypalmitic acid methyl ester

It
was show that 3-OH oxylipins can effect quorum sensing in Candida albicans
(Nigam
S et al., Curr Microbiol 2010, 62, 55), a function used by microorganisms
to measure population density and to regulate pathogenicity. Thus, this yeast
utilises 3-OH oxylipins, i.e. 3-OH-14:2 produced from 18:2, as a signal for
expression of genes responsible for accelerating cell morphogenesis at a certain
population density.
It was also found that this yeast converts arachidonic acid, released from infected
host cells, to a 3-OH oxylipin (3-hydroxy eicosatetraenoic acid or 3-HETE) via
incomplete mitochondrial beta-oxidation. This compound then acts as substrate
for the host cyclooxygenase-2 (COX- 2), leading to the production of potent
pro-inflammatory 3-OH prostaglandin E2 (Ciccoli
R et al., Biochem J 2005, 390, 737).

w-Hydroxy
acids have their hydroxyl group at the methyl end of the carbon chain and
can result in special glycerides with more than three acyl groups through acylation
of one or more hydroxyl groups (ergot, Lesquerella and kamala oils).
They participate also in the structure of suberin,
a lipid polyester present in plant cell walls, and of cutin, a lipid polyester
which is a component of the plant cuticle. These apoplastic structures are important
plant-environment interfaces which act as barriers limiting water and nutrient
loss and protecting plants from radiation and pathogens. After experimental
depolymerization, monomers and oligomers containing glycerol are esterified
by several hydroacids. The most frequent w-hydroxy
acids were found to be C16, C:18, C18:1, C18:2 in cutin and C18 to C24 in suberin
(Graca
J et al., Phytochemistry 2002, 61, 205; Graca
J et al., Chem Phys Lipids 2006, 144, 96;
Pollard M et al., Tr Plant Sci 2008, 13, 236). In lipid polyesters extracted
from Arabidopsis and Brassica seeds, w-hydroxy acids with 16 up
to 26 carbon atoms were described (Molina
I et al., Phytochemistry 2006, 67, 2597).
w-Hydroxy acids are the main building blocks of algaenan, the highly cross-linked
constituent of the cell walls of green algae (Blokker P et al., Phytochemistry
1998, 49, 691). These ester-bound fatty acids are unsaturated, the monoene
(n-9) having a C30, C32 or C34 carbon chain and the diene (n-18 and n-19) having
a C30 and C32 carbon chain.

w-hydroxy
decenoic acids occur in honey in small concentrations but are characteristic
of the royal jelly of nurse bees (Apis mellifera). trans 10-Hydroxy-2-decenoic
acid is considered as the genuine fatty compound of royal jelly (about 50 %
of the total fatty acids) (Bloodworth BC, J AOAC Int 1995, 78, 1019),
other hydroxylated fatty acids (10-hydroxydecanoic acid and 9-10-hydroxy-2-decenoic
acid, 3,10-dihydroxydecanoic acid, 8-hydroxyoctanoic acid)
were also detected. These pheromone components which are excreted in the salivary
glands of bees are said to give specific therapeutic properties to royal jelly
such as skin protection, bactericide, anti-inflammatory action, immuno-regulation
and anti-cancer activities. Furthermore, they could be potential candidates
in the treatment of atherosclerosis (Makino
J et al., J Nat Prod 2016, 79, 1137). It has been shown that worker
bees secrete acids functionalized at the last (w) position, such as 10-hydroxy-2-decenoic
acid and its saturated counterpart, while the honeybee queen produces pheromones
such as 9-hydroxy-2-decenoic acid, and other acids functionalized at the penultimate
(w-1) position (Plettner E et al., Science 1996, 271, 1851).

Several parent molecules have been described in the royal jelly (Noda
N et al., Lipids 2005, 40, 833). It has been found that these hydroxy
fatty acids strongly activate the transient receptor potential ankyrin 1 (TRPA1)
and vanilloid 1 (TRPV1) (Terada Y et a., J Agric Food Chem 2011, 59, 2627).
These properties could be related to the observed effects of royal jelly on
several pathologies.
Besides these compounds, other fatty acids were observed : a diacid, and mono-
and diesters of 10-hydroxy-2-decenoic acid in which the hydroxyl group is esterified
by another fatty acid unit (estolide-like molecules). In addition, a phosphorylated
derivative was also detected (2E-decenoic acid 10-phosphate).

Different
methods have beendescribed
for determination of 10-HDAin
royal jelly, including HPLC andgas
chromatography. The report of a study using HPLC and UV detection after ultrasound-assisted
extraction may be consulted for literature review and technical aspects (Zhou
J et al., Chromatographia 2007, 66, 185).
Due to their bifunctional nature, w-hydroxy
fatty acids are used in various industrial products ranging from pharmaceuticals,
cosmetics, coatings, surfactants and general polymer building blocks (Metzger
JO et al., Appl Microbiol Biotechnol 2006, 71, 13). The biological production
of w-hydroxy fatty acids represents an emerging biotechnology (Bitto NJ et
al., Lipid Technol 2009, 21, 216).

w-Hydroxy
octadecenoic acid : kamlolenic acid
with the following structure, 18-hydroxy, 9c, 11t, 13t-18:3, is found in kamala
oil, a product extracted from the seeds of Kamala tree (Mallotus phillipinensis,
Euphorbiaceae) (Calderwood RC et al., J Sci Food Agric 1954, 5, 382). The
kamala oil can be used as a substitute for tung oil, obtained from Aleurites
spp., in the production of rapid-drying paints and varnishes. The seed oil
is also used as a fixative in cosmetic preparations. The oil is also used as
a fixative in cosmetic preparations and for coloring foodstuffs and beverages.

A large array of hydroxylated fatty acids deriving from linoleic acid, a-linolenic
acid, roughanic acid (16:3 n-3), and other C20 fatty acids (arachidonic acid,
EPA), mainly under the action of lipoxygenase, are named Oxylipins (Mosblech
A et al., Plant Physiol Biochem 2009, 47, 511). The previously
formed hydroperoxides are subsequently transformed by the action of different
enzymes into these hydroxylated fatty acids but also into oxo fatty acids, divinyl
ethers, volatile aldehydes, and jasmonates.
They are widespread in nature occurring in plants, mosses, algae, bacteria,
fungi and sometimes in animals. In general, oxylipins are bioactive metabolites
involved in regulating developmental processes and in environmental and pathological
responses.

Very-long-chain fatty acids (C28–C34) containing a hydroxy group at the n-18
position have been identified in the microalgae from the genus Nannochloropsis
(Gelin F et al., Phytochemistry, 1997, 45, 641). That constant position
likely indicates that the series results from chain-elongation of a particular
hydroxy fatty acid. Several hydroxylated fatty acids with 16 and 18 carbon atoms
have been described in microalgae, the most abundant being hydroxylated on the
C11, C8, and C13 (de
los Reyes C et al., Phytochemistry 2014, 102, 152). These
compounds are frequently inhibitors of the TNF-a production. Thus, the most
active oxylipin was a C-16 hydroxy acid, which at 25 mM caused a 60% decrease
of the TNF-a
level in LPS-stimulated macrophages.

An oxylipin, 15-hydroxylinoleate, has been isolated from seeds of oat
(Avena sativa) and was named avenoleic acid (Hamberg M et al., Phytochemistry
1996, 42, 729). That fatty acid seems specific for oat, as it was not detectable
in seeds of barley, rye, or wheat. Further studies have shown that avenoleic
acid was found to be mainly localized in the glycolipid fraction of oat seed
lipids (Hamberg
M et al., Lipids 1998, 33, 355).

Among the 12-hydroxy acids, the most abundant is ricinoleic
acid (12-hydroxy-9-octadecenoic acid) which characterizes
castor oil (from Ricinus
communis). It was discovered in 1848 (Saalmüller L, Ann 1848, 64,
108). Goldsobel AG (Ber 1894, 27, 3121) showed that ricinoleic
acid has the actual molecular structure. This acid is the only one hydroxylated
fatty acid used in oleochemical industry. The seed oils of Jatropha gossypifolia
and Hevea brasiliensis (Euphorbiaceae living in South America and India)
were found to contain high content of ricinoleic acid (about 18%).

Ricinoleic
acid is abundant in castor oil (90%) but many common vegetable oils and oil
seeds contain lower amounts of that particular fatty acid. Thus, its content
amounts to 0.27% in cottonseed oil, 0.03% in soybean oil, and 0.02% (Yamamoto
K et al., Lipids 2008, 43, 457).
While known chiefly as a purgative, few decades ago, this fatty acid affords
now a wide range of reactions enabling the formation of several derivatives.
These chemicals are on a par with petrochemical products for use in several
industrial applications. Castor oil and its derivatives are used in food (additive),
textile (surfactants, pigment wetting agents), paper (defoamer, water proofing
additive), plastics (Nylon-11, polyamide resin known as Rilsan 11 used for coating
metals, plasticizers, coupling agents, tubes, films), perfumes and cosmetics
(emulsifiers, deodorant), electronics (capacitor fluids, polyurethane and polyamide
resins), pharmaceuticals, paints, inks, adhesives and lubricants. Castor oil
is also used to make emulsifier after transesterification of fatty acids from
the glycerol to the hydroxyl group in ricinoleic acid and ethoxylation to give
castor oil polyethylene glycol (Diehl B, Lipid technol 2011, 23, 278).
The production of conjugated linoleic acid by dehydration and isomerization
of ricinoleic acid has been described (Villeneuve P et al., JAOCS 2005, 82,
261).
Castor oil can be reacted with sulfuric acid to make Turkey-Red Oil, the first
synthetic detergent or surfactant after ordinary soap, a predecessor to sodium
lauryl sulfate. These properties are the result of the sulfonation of ricinoleic
acid. Turkey-Red Oil is also used in the dyeing of cotton texture.
The limited amount of castor oil as natural source of ricinoleic acid has led
chemists to develop suitable processes for the preparation of hydroxy fatty
acids from commercial plant oils (Dahlke B et al., JAOCS 1995, 72, 349).
The microbial transformation of ricinoleic acid with the yeast Yarrowialipolytica yields g-decalactone, an aroma compound with fruity and oily
notes found naturally in fruits and fermented foods ( Schrader J. et al.,
Biotechnol Lett 2004, 26, 463).

A fatty acid isomeric with ricinoleic acid, 9-hydroxy-12c-octadecenoic acid,
has been shown to be of general occurrence (between 9 and 15%) in the seed oils
of the genus Strophantus (Apocynaceae) (Gunstone FD et al., J Sci
Food Agric 1959, 10, 522) but was also found in Holarrhena, Nerium
and Wrightia of the same family. It was reported for the first time in
the seed oil of the desert rose Adenium obesum in which it is present
at a level of around 26 % (Smith MA et al., JAOCS 2016, 93, 105).
This fatty acid was named strophantus acid and it is a potential renewable
feedstock for the oleochemical industry, mainly as a precursor for the synthesis
of antimicrobial compounds.

As castor seed production presents some problems (toxicity of the seed, allergic
reactions), Lesquerella
species were proposed as a valuable source in the USA (up to 70% in the oil)
of ricinoleic acid but also of lesquerolic acid, the C20 homologue
of ricinoleic acid (14-hydroxy-11-eicosenoic acid). One of the most studied
species isPhysaria fendleri, formerly Lesquerella fendleri, Brassicaceae.
That plant is a new industrial oilseed crop in the southwestern region of the
U.S. can also be used for industry similar to those of ricinoleate and it is
amenable to Agrobacterium-mediated transformation to increase the lesquerolic
acid production (Wang W et al., Plant Cell Tissue Organ Cult 2008, 92, 165).
The identification of triacylglycerol and diacylglycerol species in the seed
oil of Physaria fendleri using mass spectrometry has been reported (Lin
JT et al., J Am Oil Chem Soc 2013, 90, 1819). In these species, two other
hydroxylated fatty acids are found : densipolic acid (12-hydroxy-9,15-octadecadienoic
acid) and auricolic acid (14-hydroxy-11,17-eicosadienoic acid) (Smith
CR et al., J Org Chem 1962, 27, 3112). Densipolic acid is present in triacylglycerols
of Lesquerella lyrata and forms estolide complexes (tetraacylglycerol)
when esterified by another normal fatty acid (triacylglycerol-estolides) (Zhang
H et al., Ind Crops Prod 2012, 37, 186). Thirteen tetraacylglycerol species
have been detected in Physaria fendleri (Lin JT et al., J
Am Oil Chem Soc 2013, 90, 1831).

11-Hydroxy hexadecanoic acid, or jalapinolic acid, occurs in jalapin
(resin from the rhizoma of Ipomea operculata) and in scammoniae resina
(resin from the roots of Convolvulus scammonia). The main components
containing jaliponoic acid in these resins are
operculinic acids (Ono M et al., Chem Pharm Bull 1990, 38, 2650).

9-Hydroxyacid : another unusual hydroxylated fatty acid
which may have many potential oleochemical applications has been discovered
in munch seed oil (Dimorphotheca
pluvialis) : b-dimorphecolic
acid (9-hydroxy,10t,12t-18:2) (Smith CR et al., J Am Chem Soc 1960, 82,
1417). This compound which is also a conjugated diene seems to be a versatile
raw material for applications in chemical, pharmaceutical, flavor and fragrance
industries since it can be readily dehydrated to a mixture of conjugated triene
acids. The 10t12c form of the 9-hydroxy-18:2 (isomeric with dimorphecolic acid)
is present in the seed oil of Xeranthemum
annuum, Dimorphotheca, Tragopogon, Tagetes, Bidens and Cosmos. This
compound was shown to be a
partial agonist at PGEl and PGD2 receptors on human platelets (Henry DY et
al., Eur J Biochem 1987, 170, 389).
Dimorphecolic acid has been isolated in relatively pure state by supercritical
carbon dioxide extraction of munch seed oil (Cuperus FP et al., JAOCS 1996,
73, 1675).
Another isomeric form of dimorphecolic acid, coriolic acid (13-hydroxy-9c,11t-octadecadienoic
acid), was reported to be present at high level (70%) in the seed oil of a Coriaraceae
Coriaria myrtifolia (Hanseen KS et al., Acta Chem Scand 1967, 21,
301) but also in a Polygonaceae Monnina emerginata (30%) (Phillips
BE et al., Biochim Biophys Acta 1970, 210, 353).

A wide range of hydroxylated fatty acids is found in sediments but unfortunately
these compounds have received little attention from organic geochemists. Long-chain
up to C24 and a- and b-monohydroxy acids were observed in a 5000 year-old lacustrine
sediment from the English Lake district (Eglinton G et al., Tetrahedron 1968,
24, 5929), and were attributed to microbial oxidation of monocarboxylic
fatty acids.

Analytical works on the seed oil of Ongokea gore (Olacaceae)
have demonstrated the existence of a variety of hydroxylated diynoic acids
(review in Badami RC et al., Prog Lipid Res 1981, 19, 119). Some of them
have no other double bond as 8-hydroxyoctadeca-9,11-diynoic acid, others have
in addition one double bond as isanolic acid or two double bonds as
8-hydroxyoctadeca-13,17-dien-9,11-diynoic acid.

POLYHYDROXY FATTY ACIDS

A long-chain dihydroxy fatty acid has been found in an Euphorbiaceae Baliospermum
axillare seed oil and characterized as 11,13-dihydroxy-tetracos-9t-enoic
acid (Husain S et al., Phytochemistry 1980, 19, 75). It was named axillarenic
acid.
Two dihydroxy fatty acids have been isolated from floral oils produced by
various flowers (Mariza R et al., J Chem Ecol 2007, 33, 1421). These
fatty acids (3,7-dihydroxy-eicosanoic and docosanoic acids) were named tetrapedic
acids. One of them (3,7-dihydroxy-docosanoic acid) may be di-acetylated, and
was named byrsonic acid. These fatty acids were also found acylating a
mono-acylated glycerol molecule. These oily compounds are produced by special
flower devices (elaiophores) and attract pollinating insects. Two dihydroxy fatty acids, 15,16-dihydroxy-30:0 and 16,17-dihydroxy-33:0,
have also been identified from the acid hydrolysis of the cell residue of Nannochloropsis.

The seed oil of Cardamine impatiens (Cruciferae, Brassicaceae) contains a
series of long-chain vicinal dihydroxy fatty acids which make up of about 25% of
the oil (Mikolajczak KL et al., JAOCS 1965, 42, 939). This peculiar
structure remains unique in phytochemistry. One example with a C18 chain is
shown below. Other members of the series have a C20, C22 or a C24 chain but with
the hydroxyl groups remaining at the same position with respect to the terminal
methyl group. 9,10-dihydroxyoctadecanoic acid was also found at 11% in the seed
oil of a Rutaceae Feronia elephantum (Badami RC et al., J Oil Tech
Assoc India 1972, 4, 59).

An
isomeric form of the previous one but not with vicinal hydroxy groups has been
described in the seed oil of a Rutaceae Peganium harmala, 9,14-dihydroxyoctadecanoic
acid (Ahmad I et al., Phytochemistry 1977, 16, 1761). Cutin is known to be a polyester polymer which is insoluble and can be
hydrolyzed mainly into a mixture of long-chain C16 and C18 w-hydroxyacids
having frequently hydroxyl or epoxy groups in secondary positions. Phellonic
acic, 22-hydroxydocosanoic acid, was also detected in cork suberin. Several
studies led to tentative models of cutin based on the inter-esterification of
w-hydroxyacids, both head-to-tail in a linear form , and cross-linked via the
secondary hydroxyls. In some plant species cutin, 16-carbon dihydroxy and 18-carbon
trihydroxyacids were detected (Graca J et al., Phytochemistry 2002, 61, 205). Suberin is a similar type of polyester
polymer which contains among other fatty acids a,w-diacids
as long-chain monomers esterifying glycerol (Graca J et al., Chem Phys
Lipids 2006, 144, 96). Moreover, these diacids (C16, C18, C18:1, and C22)
are further esterified by another glycerol molecule or by a hydroxylated fatty
acid.

A
monounsaturated derivative of phloionolic acid was also detected in some seed
oil.
Higher plant cutin and suberin can also be a significant source of esterified
C16-C22 a-,
b-, and w-monohydroxy and C16 and C18 polyhydroxylated fatty acids in sediments
(Cardoso JN et al.,Geochim Cosmochim Acta 1983, 47, 723).

Estolides are dimers formed by a normal fatty acid esterifying
a hydroxy fatty acid. They are found mainly in some special triglycerides where
they acylate the sn-3 position and formed estolide tetraester triglyceride.
They are found in seed oil from Euphorbiaceae. A hydroxy allenic acid
(8-hydroxy-5,6-octadienoic acid) was described in an estolide from Sebastiana
commersoniana (Spitzer
V. et al. Lipids 1997, 32, 549). The w-hydroxyl group was shown to be
acylated by a conjugated diene with 10 carbon atoms.

The allenic acid was shown to have
antifungal properties (Ohigashi H et al Agr Biol Chem 1972, 36, 1399),
the triglyceride being not recommended for animal diet.
Original estolides, named mayolenes, have been isolated from the glandular hairs
of a caterpillar (Pieris rapae) (Smedley
SR et al., PNAS 2002, 99, 6822).

Mayolenes (n = 9 to 15)

These estolides
are formed by a 11-hydroxylinolenic acid esterified by a saturated fatty acid
(C14-C20). Bioassays demonstrated that they are potent deterrent, playing a
defensive role against predators.
Lipidomic analysis of mouse adipose tissue revealed the existence of estolides
that were elevated 16- to 18-fold in these mice. Several isomers differ by the
branched ester position on the hydroxy fatty acid (e.g., palmitic acid-9-hydroxystearic
acid). These estolides are synthesized in vivo and regulated by fasting and
high-fat feeding. Their level correlates highly with insulin sensitivity and
are reduced in adipose tissue and serum of insulin-resistant humans, These compounds
could have the potential to treat type 2 diabetes (Yore
MM et al., Cell 2014, 159, 318).

Besides classical wax esters, the secretions of the human Meibomius glands (meibum)
which are mixed with tears, contain estolides based on a w-hydroxylated
fatty acid (mainly from 30 to 34 carbons) acylated on the terminal hydroxyl
by oleic acid (18:1n-9) (Butovich IA et al., J Lipid Res 2009, 50, 2471).
Due to their amphiphilic anionogenic nature, these compounds may be responsible
for stabilization of the tear film lipid layer.

w-Estolide from meibum

Industrially, estolides are now synthesized from vegetal oils and are used as ingredients in
various industrial fields. Thus, these new functional fluids have a rapidly growing importance in
cosmetics, coatings, and biodegradable lubricants.

They are largely synthesized from oleic acid warmed with
perchloric or sulfuric acid (Cermak SC et al. JAOCS 2001, 78, 557). The
average number of fatty acid units added to the first base fatty acid (named
"estolide number") varied as
a function of reaction temperature. The secondary ester linkages are more
resistant to hydrolysis than those of triglycerides, and the unique structure of
the estolide results in materials having far superior physical properties than
mineral oils and vegetable and petroleum-based oils. They are said to improve intra-fiber moisture retention, to
restore elasticity, and prevent mechanical damage. In skin care systems, they provide significant moisturization benefits.
Estolides made from vegetal oils have a good oxidative stability and
low-temperature properties. Oxidative stability may be improved in removing the
unsaturation of oleic acid and the low-temperature performance may be improved
in using oleic acid and various short or middle-chain saturated fatty acids (lauric
or myristic acid, coconut oil). Other chemical developments are in progress to
obtain molecules with required functional fluid conditions (Cermak S et al.,
Inform 2004, 15, 515).
The analysis of these compounds may be effected by a combination of gel
permeation chromatography, TLC, and gas chromatography (Fehling E, JAOCS
1995, 72, 355).
A kind of estolide has been described in the stem bark of an Euphorbiaceae (Alchorena
laxiflora), a plant used in Africa to treat some diseases (Sandjo LP et
al., JAOCS 2011, 88, 1153). That compound is formed of a C14
fatty acid with a double bond in the n-3 position esterified with a hydroxylated
propionic acid.

Estolide from Alchorena

Macrolactins are macrolides
containing three separate diene structure elements in a 24-membered lactone ring
which were first reported to be produced by several marine bacteria (Gustafson
K et al., J Am Chem Soc 1989, 111, 7519). Several macrolactin structures
have been described in marine bacteria, the simplest one (macrolactin A) is
shown below.

Macrolactin A

These antibiotics may be considered
equivalent to a tetrahydroxylated tetracosaenoic acid with an ester bond between the
carboxyl group and one of the hydroxyl groups (lactone structure). They are considered to
be potent antiviral (against herpes and HIV) and cytotoxic (against melanoma)
agents that also have antibacterial activity.It
was suggested that the hydroxyl group at C-15
may play an important role in the antibacterial activity of these compounds. There is
yet no information about the mechanism of action of this
group of compounds.

Parcoblattalactone is a macrocyclic lactone deriving from a 12-carbon fatty acid
hydroxylated in position w.
This compound is a sex pheromone of the insect Parcoblatta lata, which
represents the most abundant arthropod biomass in the pine forests of the
southeastern United States (Eliyahu
D et al., PNAS, 2012, 109, 490-6). This pheromone will be used for
monitoring populations of insects that comprise an important food source for
endangered bird species.

Parcoblattalactone

Lipoxygenase
activities give rise to important hydroxylated derivatives mainly from polyunsaturated
fatty acids.
Thus, lipoxygenation of 20:4(n-6) results in the formation of a variety of mono-
and dihydroxy derivatives. The monohydroxy derivatives consist of the positional
isomers 5-hydroxy-20:4, 12-hydroxy-20:4 and 15-hydroxy-20:4. The dihydroxy derivatives
include products arising from 5- or 15-lipoxygenation. Double lipoxygenation
of 20:4(n-6) at c5 or c12 position give rise to 5,12-diHETE.
In addition to 20:4(n-6), linoleic acid (18:2n-6) is also a substrate for lipoxygenases.
In leucocytes (neutrophiles), 13-hydroxy-18:2 (coriolic acid) is produced through
enzymatic activity. It appears to be also produced by vascular endothelial cells
where it prevents platelet attachment and has vasoconstrictor activity.

Allium species (onion and garlic) which are known as folk medicine
for the treatment of atherosclerosis and some ulcers, were shown to be rich
in two trihydroxylated derivatives of 18:2(n-6) : 9,10,13- and 9,12,13-trihydroxy
octadecenoic acids. Furthermore, it was shown that these products have PGE-like
activity in in vitro bio-assay tests (Claeys M et al., Prog Lipid
Res 1986, 25, 53). Similar products were isolated from roots of Bryone
ala, used also for similar medicinal purposes as onion (Panossian AG
et al., J Med Plant Res 1983, 47, 17).

Lipoxygenase derivatives of docosahexaenoic acid (DHA),
named docosanoids, are known to be formed (mainly 11-OH-DHA) in retinal
cells (Bazan
N et al., Biochem Biophys Res Comm 1984, 125, 741), but their exact
structure and bioactivity were revealed only after 2002. A review of their formation
and function in blood and vascular cells may be consulted (Lagarde M, Eur
J Lipid Sci Technol 2010, 112, 941). A critical overview on the dihydroxy-docosatrienes
may be also consulted (Balas
L et al., Biochimie 2014, 99:1-7) and their roles in metabolic diseases
has also been reviewed (Spite
M et al., Cell Metab 2014, 19, 21).

Biosynthetic pathways and structures of
resolvins, protectins, and maresins generated enzymatically from DHA

On
another hand, brain ischemia was shown to induce a release of DHA from membrane
phospholipids which then generates via enzymatic oxygenations novel derivatives
named "docosatrienes". These dihydroxy-containing DHA derivatives
were termed "neuroprotectins".
The main member of the series was 10,17S-docosatriene (neuroprotectin D1) which
was proved to be a potent regulator of inflammation (Marcheselli
VL et al., J Biol Chem 2003, 278, 43807).

Neuroprotectin D1

Several isomers of protectin D1 were synthesized using soybean lipoxygenase
and tested for their ability to inhibit human blood platelet aggregation. It
was discovered that the oxygenated products having the E,Z,E-conjugated triene
motif and collectively named poxytrins (PUFA oxygenated trienes), might have
potent antithrombotic potential (Chen
P et al., FASEB J 2011, 25, 382).

The biosynthetic pathway of that DHA derivative in retinal pigment cells and
its protective effects from apoptosis induced by an oxidative stress were reported
(Mukherjee
PK et al., PNAS 2004, 101, 8491). These compounds may be the basis
of new therapeutic approaches to enhance photoreceptor survival in retinal degenerations.
A review of the rescue and repair processes during photoreceptor cell renewal
mediated by neuroprotectin D1 may be consulted (Bazan
NG et al., J Lipid Res 2010, 51, 2018).
Some isomers exhibiting the 11t,13c,15t geometry, instead of 11t,13t,15c as
in protectin D1 (poxytrins family), are able to inhibit strongly blood platelet
aggregation (Chen
P et al., FASEB J 2011,25, 382).
Besides 10,17S-docosatriene, the
analogue compound 7,17S-docosatriene was shown to be produced during aerobic
oxidation of DHA by soybean lipoxygenase (Butovich
IA et al., J Lipid Res 2006, 47, 2462). Enzymatic investigations suggest
that these compounds might have anti-inflammatory and anticancer activities,
which could be exerted, at least in part, through direct inhibition of 5- and
15 lipoxygenase. An overview of their role in brain physiology and a discussion
on the potential of using DHA signaling in the development of treatments in
patients suffering from stroke have been released by Niemoller
TD et al. (Prost Lipid Mediat 2010, 91, 85).

One neuroprotectin and several resolvins have been shown to be biosynthesized
by isolated trout brain cells providing the first evidence for the conservation
of these structures from fish to humans as chemical signals in diverse biological
systems (Hong
S et al. Prost Lipid Mediat 2005, 78, 10).

This resolvin was shown to be
a potent regulator of PMN cells and inflammation (Serhan
CN et al., Prost Lipid Med 2004, 73, 155). New resolvins derived from docosapentaenoic
acid of the n-6 family (22:5n-6) have been characterized (Dangi
B et al., J Biol Chem 2009, 284, 14744). These products resulting from 15-lipoxygenase
activity were determined to be potent anti-inflammatory agents.
A comprehensive review of the metabolism and properties of resolvins, docosatrienes
and neuroprotectins may be consulted (Serhan
CN et al., Lipids 2004, 39, 1125). An overview of their synthesis and their
biological significance have been reviewed (Balas
L et al., Prog Lipid Res 2016, 61, 1-18). A review of the importance of
polyunsaturated fatty acids and their oxygenated or hydoxylated metabolites
in the blood vessel compartment may also be consulted (Lagarde
M et al., Prog Lipid Res 2015, 60, 41).

-Thia
fatty acids : sulfur-substituted fatty
acid analogues are actively synthesized as they are reported to have important
pharmacological properties (antiatherosclerosis and antioxidant).
They can have a variable number of carbon atoms and the sulfur atom in different
position (3-thia or 4-thia).
The most commonly 3-thia fatty acids studied are presently:

Isomeric epithio stearic acids have been described as minor constituents in
canola oil. They were tentatively identified were the 9,12; 8,11; and 7,10 epithio
stearic acids (Wijesundera RC et al., JAOCS 1988, 65, 959). The general formula
is given below.

x = 5, 6 or 7 and y = 7, 6 or
5, respectively

- Sulfated fatty
acids : New
fatty acid derivatives have been isolated from the regurgitant of the
grasshopper species Schistocerca americana. These compounds (named
caeliferins) are composed of saturated and monounsaturated sulfated a-hydroxy
fatty acids in which the w-carbon
is substituted with a sulfated hydroxyl group (Alborn
HT et al., PNAS 2007, 104, 12976). These compounds have a carbon chain
of 15–20 carbons and are distributes in varying proportions. Of these, the 16:1
analog is predominant and is also the most active in inducing release of
volatile terpenoid compounds when applied to damaged leaves of corn seedlings.

Caeliferin A 16:1

FATTY ACID AMIDES

Fatty acid amides are natural products formed by
connecting straight-chain, mostly unsaturated, aliphatic acids with various
amines by an amide linkage. More than 300 derivatives are known from eight plant
families consisting of various combinations of 200 acids with 23 amines.
These compounds are found in nature, but are seldom encountered in fats and
oils. As many other nitrogen derivatives of fatty acids (amino acids, hydrazides,
acid azides, nitriles, isocyanates, amines), they are of considerable interest
and economic importance and have, therefore, been the object of much research
and industrial attention mainly in the 50s. They are now produced on a large
scale, their chemical features resulting in high surface activities. These compounds
are useful as fiber lubricants, detergents, flotation agents, textile softeners,
antistatic agents, wax additives, and plasticizers but some of them have also
specific biological functions.
Alkamid® is an Internet resource of plant occurring N-alkylamides (http://alkamid.ugent.be/)
managed by the Ghent University. Various data of specific molecules can be searched
for their origin and their physicochemical properties.

They have a wide variety of biological activities ranging from the characteristic
pungent/tingling property and high insecticidal toxicity to significant antifungal,
antibacterial, antiprotozoal, molluscicidal, cercaricidal, and acaricidal activity.
They also act as plant growth-promoting substances. Some of them possess anti-inflammatory
and
analgesic properties and are responsible for immunomodulatory and cannabinomimetic
effects (review in: Greger H, Phytochem Rev 2016, 15, 729).

The simple amides may be considered to be products resulting from replacement
of the hydroxyl of the carboxyl group with an amino group, RCONH2.
The first preparation of stearamide was made in 1882 (Hofmann
AW, Ber. 1882, 15, 977) using the procedure of thermal dehydration of ammonium
salts discovered by the famous French chemist Dumas (Dumas J, Ann chim phys
1830, 44, 29).

Fatty acid alkanolamides are industrially produced from fatty acids (largely
from coconut oil) and alkanolamines, such as ethanolamine, by heating at about
150°C for 6-12 h (Feairheller SH et al., JAOCS 1994, 71, 863).

R-CO-NH-CH2-CH2-OH

They can also be produced from
plant erucic acid treated with ammonia.
These compound have a broad spectrum of uses, e.g., in shampoos, detergents,
cosmetics, lubricants, foam control agents, and water repellents (Sanders
HL, JAOCS 1958, 35, 548), and for the production of nonsticking plastic
films and protective coatings.

Simple amides of fatty acids (alkylamides) were shown to be very potent
bio-effectors. For example, in chicken chorioallantoid membrane and rat cornea,
it was shown that amide of 13-cis-docosenoic acid (erucamide)
discovered in the bovine mesentery is an angiogenic factor (Wakamatsu K
et al., Biochem. Biophys. Res. Commun., 1990, 168,423). Angiogenic activity
(induction of capillary development) was demonstrated by synthetic primary amides
of 13-t-docosenoic acid, 18:0, 20:0, 22:0, 20:4n-6, and to a lesser extent of
16:0, 18:1n-9.
The amide of 9-octadecenoic acid (oleamide) was isolated from
the cerebrospinal fluid of sleep-deprived cats.

This compound is recognized now to
be the endogenous factor inducing sleep in mammals (Cravatt, B F et al.,
Science, 1995, 268, 1506). Rats treated with oleamide fall
asleep. It seems that oleamide may have many other physiological functions,
including thermoregulation and sensitivity to pain.
Oleamide is synthesized by the brain cells from oleic acid and ammonium (Sugiura,
T et al., Biochem. Mol. Biol. Int., 1996, 40, 93) and its level is regulated
by a fatty amide hydrolase which degrades the amide to oleic acid. Apart from
its effect on the central nervous system, oleamide modulates the function of
the immune cells.
Unexpectedly, oleamide is an important pheromone attractant of the hermaphroditic
shrimp Lysmata boggessi.(Zhang
D, et al., PLoS One, 2011, 6, e1772064). It is located on the cuticle and
its bioactivity is enhanced when incorporated as a pheromone blend with hexadecanamide
and methyl linoleate.
Primary amides were identified in the cuticle of Phyllostachys aurea
leaves, with a characteristic chain length profile
peaking at C30. The amides were present exclusively in the epicuticular layer
and thus at or near the surface, where they may affect plant-herbivore or plant-pathogen
interactions (Racovita
RC et al., Phytochemistry 2016, 130, 252).

Cerulenin is an antifungal antibiotic discovered in
the culture filtrate of Cephalosporium caerulens (Matsumae A et al.,
J Antibiot (Tokyo) 1963, 16, 236) and shown to inhibit fatty acid biosynthesis
(Vance D et al., Biochem Biophys Res Commun 1972, 48, 649). This epoxy-fatty
amide has 12 carbon atoms, two double bonds and an epoxy ring. The inhibition
of the fatty acid synthase by cerulenin leads to cytotoxicity and apoptosis
in human cancer cell lines, effect which suggested a possible cancer treatment.
It blocks the synthesis of polyketides in a wide variety of organisms and has
a wide range of antimicrobial activity inhibiting the growth of yeast-like fungi,
such as Candida, Saccharomyces and Cryptococcus.

Cerulenin

Many bioactive lipids containing
a fatty acid linked to an amine-containing compound are found in animal
organisms and are described in the simple lipid section.
Much attention has been given to that class of compounds. Briefly, the
origins of this research can be traced to 1957 when Kehul FF et al.J
Am Chem Soc 1957, 79, 5577)
identified N-palmitoylethanolamine as an anti-inflammatory factor present in
egg yolk, soybeans, and peanuts. Renewed interest in this and similar N-acylethanolamines
arose with the discovery of N-arachidonoylethanolamine (anandamide). An
overview of the biochemistry and pharmacology of anandamide
has been released (Hansen HS et al., Eur J Lipid Sci Technol 2006,
108, 877).

Thus, simple lipoamino acids with an
amide link between one fatty acid and one aminoacid (serine, ornithine, thyrosine,
glycine, proline or leucine) or domamine or aminoalcohol (anandamide)
are described. <

A review on the role played by these molecules in pain modulation has been released
by Walker JM et al. (Prost Lipid Med 2005, 77, 35).

Fatty acid amides are found in grasses and microalgae. Hexadecanamide and octadecanamide
were isolated from the shoots of marine grass Zostera marina (Kawasaki
W et al., Phytochemistry 1998, 47, 27). 9-Octadecenamide was identified
and quantified (about 2.3% of total fatty acids) among others in the green alga
Rhizoclonium hieroglyphicum (Dembitsky VM et al., Phytochemistry 2000,
54, 965). The cyclopropyl fatty amide, grenadamide, was detected from the
cyanobacterium Lyngbya majuscula (Sitachitta N et al., J Nat Prod
1998, 61, 681) and a branched-chain fatty amide was isolated from the dinoflagellate
Coolia monotis (Tanaka I et al., J Nat Prod 1998, 61, 685).
Several alkylamides have been isolated from Echinacea sp (Asteraceae),
one of the most popular medicinal plant used for treatment and prevention of
common cold and respiratory tract infections (Woelkart
K et al., Planta Med 2007, 73, 615). These alkylamides differ in chain
length and unsaturation, many having a diynoic structure. They show structural
similarity with anandamide and pharmacological studies have shown that they
bind significantly to cannabinoid (CB2) receptors.

A method for the isolation of C18 fatty acid amides from lipid extracts and
their analysis by mass spectrometry was reported (Sultana
T et al., J Chromatogr A 2006, 1101, 278). The simultaneous quantification
of anandamide and other endocannabinoids in brain tissue has been reported (Chen
J et al., Chromatographia 2009, 69, 1).

Several benzyl alkylamides (macamides) were isolated from maca
(Lepidium meyenii) lipid extract. Tubers of that plant, used as food
in Peru and as dietary supplements ("Peruvian ginseng") elsewhere,
contain macamides which could have promising biological activities. The simplest
structure, described in 2002 (Zhao J et al., Chem Pharm Bull 2002, 50, 988)
is shown below.

Analogous structures with various chain
lengths, unsaturation or substitutions (methoxy or keto group) were also
described in the same material (Zhao J et al., J Agric Food Chem 2005, 53,
690).

Similar structures, 11-Cyano or 11-thiocyanato undecanoic acid
phenylamide, have been synthesized as corrosion inhibitors to prevent the
corrosion of metals in acidic media (Yildirim A et al., Eur J Lipid Sci
Technol 2008, 110, 570). These molecules generate a protective layer by
adsorption to the metal surface via electrons present on their heteroatoms (0,
S, N).

More complex fatty acid amides (one of them is shown below) were discovered in
leaves of Chrysanthemum morifolium (Compositae). These
isobutylamides, having one or two acetylenic bonds and three or four double
bonds, were associated with host-plant
resistance against a major insect pest facing greenhouse industry (Frankliniella
occidentalis) (Tsao R et al., J Nat Prod 2003, 66, 1229).

The N-alkylamides dodeca-2,4-dienoic acid (1) and dodeca-2,4,8,10-tetraenoic (2) acid
isobutylamides from the plant purple coneflower Echinacea were shown to
be likely responsible for the early treatment for colds and as immunostimulants
(Gertsch
J et al., FEBS Lett 2004, 577, 563).

The isobutylamide of deca-trans-2,trans-4-dienoic acid, isolated
from the roots of Piper nigrum and various Asteracaea, is a modulator
of the sensory neuron function. It is an efficient model compound for sensory
studies but also for diabetes, cancer, infection and inflammatory research.
The isobytylamide of deca-trans-2,cis-6,trans-8-trienoic
acid (Spilanthol), isolated from several species of Spilanthes, is
likely responsible for the anesthetic properties of these plants.

Natural alkylamides, called sanshools, are found in
the pericarp of the fruit of Szechuan pepper (Menozzi-Smarrito
C et al., J Agric Food Chem 2009, 57, 1982). Four sanshools were described
in that fruit, they differ from the configuration of one double bond and the
length of the polyenic chain (12 or 14 carbons). Two are shown below.

One common characteristic of all these
compounds is their agonistic activity on TRPV1, consistent with their burning
properties (Sugai
E et al., Biosci Biotechnol Biochem 2005, 69, 1951).

A comprehensive review on fatty acid amides may be found on the site of
Biochimica
(Moscow). Their pharmacological properties were discussed by di Marco V (Biochim
Biophys Acta 1998, 1392, 153).

Fatty hydroxamic acids may be regarded as derivatives of both fatty acids
and hydroxylamine. Their general formula is R-CO-NHOH.

Azamacrolides are alkaloids found in defensive droplets
from glandular hairs of the pupa of the Mexican bean beetle, Epilachna varivestis
(Attygalle
AB et al., PNAS 1993, 90, 5204). Chemical studies have shown that the
major constituent of this secretion, epilachnene, is the 11-propyl-12-azacyclotetradec-5-en-14-olide.
this compound is a vary efficient repellant for ants. Its biosynthesis has been
described to be the result of a condensation of oleic acid and serine (Attygalle
AB et al., PNAS 1994, 91, 12790).

11-Propyl-12-azacyclotetradec-5-en-14-olide

METHOXY and ACETOXY FATTY ACIDS

Fatty acids may be naturally
derivatized with a methoxy or an acetoxy
group.

These monounsaturated fatty acids
were shown to have antimicrobial activity.
All these compounds were postulated to originate from bacteria in symbiosis
with sponges.

Several other saturated and unsaturated 2-methoxylated fatty acids were isolated
from phospholipids of a Caribbean sponge (Callyspongia fallax) (Carballeira
NM et al., J Nat Prod 2001, 64, 620). The saturated were identified
as 2-methoxytetra-, penta- and octadecanoic acids, the monounsaturated as 2-methoxy-6-tetra-,
penta- and hexadecenoic acids.

The 2-methoxy-13-methyltetradecanoic acid was identified, together
with other 2-methoxylated C15-C16 fatty acids, in the sponge Amphimedon complanata
from Puerto Rico (Carballeira
NM et al., Lipids 2001, 36, 83). This fatty acid is the methoxylated
analog of the bacterial 2-hydroxy-13-methyltetradecanoic acid and was shown
to be highly cytotoxic to human cancerous cells (Carballeira
NM et al., Chem Phys Lipids 2003, 126, 149). These methoxylated fatty
acids could have originated from bacteria in symbiosis with the sponge.
Two 2-methoxy fatty acids with a very long carbon chain (2R,5Z,9Z)-2-methoxy-25-methyl-5,9-hexacosadienoic
acid and (2R,5Z,9Z)-2-methoxy-24-methyl-5,9-hexacosadienoic acid were isolated
from the Caribbean sponge Asteropus niger and were shown to be effective
topoisomerase IB inhibitors (Carballeira
NM et al., Lipids 2016, 51, 245–256).

Several saturated 2-methoxylated fatty acids(from C10 to C14)
were synthesized and were shown to display some degree of inhibition of Mycobacterium
tuberculosis (Carballeira
NM et al., Lipids 2004, 39, 675).

The phospholipids of the sponge Polymastia
gleneni were shown to contain saturated long chain (C-22 to C-30)-acetoxy
fatty acids (Ayanoglu E et al., Lipids 1985, 20, 141).
In plants, several 3-acetoxy fatty acids with 14, 16 or 18 carbon atoms are
constituents of the partially acetylated acylglycerols found in floral oils
of several species of Diascia (Srophulariaceae) (Dumri K et al., Phytochemistry
2008, 69, 1372). In Calceolaria and Lysimachia, a diacylglycerol,
(1,2-di-(3-acetoxy-11-octadecenoy)-sn-glycerol) is the major floral lipid.

1,2-di-(3-acetoxy-E-11-octadecenoy)-sn-glycerol

From Byrsonima intermedia (Malpighiaceae) floral oil, a
di-acetylated
fatty acid was isolated, 3,7-diacetoxy-docosanoic acid (bryonic acid) (Reis
MG et al., J Chem Ecol 2007, 33, 1421). Several partially acetylated dihydroxy fatty acids could be identified in the
floral oil secreted by Malpighia coccigera(Malpighiaceae)(Seipold L
et al., Chem Biodiv2004,
1, 1519).
These fatty acids had a chain of 20, 22 or 24 carbon atoms and two hydroxyl
groups in various positions, one of them being acetoxylated.
Unexpectedly, these compounds characterize non-volatile oils produced in flowers
by special anatomical adaptations (elaiophores) which are collected by
pollinating bees, mainly in tropical areas of North and South America (neotropic
ecozone). The bees seem to
use these lipid secretions (instead of nectar) as provision for their
larvae. These structures, generating a "floral syndrome", were described for the first time by Vogel S in 1969 (XI
Proc Intl Bot Congress, Seattle, 1969, p. 229. Abstr). In 1987, a review on
the ecology of oil flowers and their bees (more than 400 species) listed more than 2400 species of
flowering plants (10 families) offering fatty oils (Buchmann SL, Ann Rev Ecol
Syst 1987, 18, 343).

A group of unusual triglycerides, in which one of the acyl groups is a vicinal
dihydroxy acid with one of the hydroxyl groups acetylated, has been isolated
from Cardamine impatiens (Cruciferae) seed oil. Several species were
identified : C-18, C-20, C-22, and C-24 hydroxy acetoxy fatty acids (Mikolajczak
KL et al., Lipids 1968, 3, 215).

KETO FATTY
ACIDS

Keto fatty acids are rare but one is
well known, 9-keto-2t-decenoic acid, which is an active constituent of the
royal jelly (milky substance produced by the worker honey bee).

This fatty
acid which has a pheromone role, is produced by the mandibular glands of the
queen, it attracts and controls the activities of the workers in suppressing
the queen-rearing behavior of the worker bees. Several other examples of similar
chemicals participate in animal chemoreception (Winston M et al., Am Scientist
1992, 80, 374).
9-keto-2-decenoic acid could be a stimulant of the antibiotic activities against
harmful bacteria and fungal infestations.
A new keto fatty acid, 9-keto-13-18:1(26%), was isolated from the seed oil of
Smilax macrophylla (Liliaceae) (Daulatabad CD et al., Phytochemistry
1996, 42, 889).
Rosaceae are characterized by some unusual fatty acids, among them the triunsaturated
licanic acid, 4-keto-9c11t13t-octadecatrienoic acid, which was described
for the first time in oiticica oil extracted in Brazil from Licania rigida
(Brown WB et al., Biochem J 1935, 29, 631). This keto derivative
of eleostearic acid is present at high concentration (about 60%) in Licania
seed oil (Mendelowitz A et al., Analyst 1953, 78, 704). This oil is used
as a drying oil for varnishes, and as a component in the manufacture of alkyd
resins.

The isolation and structure elucidation of an unusual fatty acid with g-oxocrotonate
partial structure have been described (Teichert A et al., Z Naturforsch 2005,
60, 25). That compound revealed fungicidal activity against the ascomycete
Phytophthora infestans, the causal agent of potato and tomato late blight
disease. That ascomycte is known as one of the most destructive pathogens worldwide
(Eschen-Lippold L et al., J Agric Food Chem 2009, 57, 9607).

(2E)-4-ketohexadec-2-enoic acid

It has been found that a ketol derivative
of linolenic acid, 9-hydroxy-10-keto-12(Z),15(Z)-octadecadienoic acid, is a
signal compound in Lemna paucicostata after exposure to stress, such
as drought, heat or osmotic stress (Suzuki
M et al., Plant Cell Physiol 2003, 44, 35). That compound reacts with
catecholamines to generate products that strongly induce flowering (Yokoyama
et al., Plant Cell Physiol 2000, 41, 110; Yamaguchi
et al., Plant Cell Physiol 2001, 42, 1201).
A new keto acid, 12-keto-5,8,10-heptadecatrienoic acid, is produced (together
with 16:4n-3) in mesenchymal stem cells treated
by chemotherapy products and was shown to be related to the induced resistance
after treatment. The formation of that keto acid, through the action of cyclooxygenase-1
and thromboxane synthase, could be a target to enhance chemotherapy efficacy
in patients (Roodhart
JML et al., Cancer Cell 2011, 20, 370).
A 20-carbon keto acid, 15-ketoeicosatetraenoic acid, was discovered to be attached
to phosphatidylethanolamine found in monocytes and macrophages (Hammond
VJ et al., 2012, 287, 41651). It was shown that that compound is able
to activate peroxisome proliferator-activated receptor-g.

OXO FATTY ACIDS

There are a number of aldehydic
fatty acids (w-oxo
acids) in plants which derive from fatty acid hydroperoxides and play important
cell signaling roles.
These molecules form the well known "traumatin" family which includes
traumatin (12-oxo-9Z-dodecenoic acid, the precursor of traumatic
acid), and
autoxidation derivatives (9-hydroxy- and 11-hydroxy-traumatin). Traumatic acid
is considered as a plant growth hormone.

t

Traumatin
hydro-derivatives were shown to be formed by a non-enzymatic oxidation process
(Noordermeer
MA et al., Biochem Biophys Res Comm 2000, 277, 112). Traumatin and other
w-oxo acids
were shown to be the products of the successive actions of lipoxygenase and
hydroperoxide lyase on linoleic and linolenic acids (Gardner
HW, Lipids 1998, 33, 745). The main biological property of traumatin
is the ability to stimulate wound healing in plants (Zimmerman et al., Plant
Physiol 1979, 63, 536). Traumatin and derivatives are likely to play a role
in defense against fungi, bacteria and arthropods (Farmer EE, Plant Mol Biol
1994, 26, 1423).

This compound was shown to be also produced by
soybean cotyledons (Kondo Y et al., Biochim Biophys Acta 1995, 1255, 9).
The heterolytic cleavage of 9- and 13-hydroperoxides in higher plants leads to
the production of traumatin and 9-oxononanoic acid (Delcarte J et al.,
Biotechnol Agron Soc Environ 2000, 4, 157).

It was shown that in mammal (rabbit
liver) another enzymatic pathway (P-450 and reductase) was also able to generate
13-oxo-9-11-tridecadienoic acid as in algae (Rota C et al., Biochem J 1997,
323, 565).